Understanding how the kidney functions to maintain normal sodium balance is particularly important because even subtle disruptions in this equilibrium play a role in most (if not all) cases of high blood pressure, that can lead to malignant hypertension, stroke or even death. The epithelial sodium channel, ENaC, is the physiologic mediator of sodium reabsorption by the kidney, and the rate-limiting step in this process as well. Recent work has shown the potential significance of a small aldosterone-regulated protein called GilZ, in profoundly stimulating the activity of ENaC, by markedly down-regulating the inhibitory ERK1/2 Mitogen Activated Protein Kinase pathway. The broad objective of this project is to systematically investigate how GilZ affects ENaC expression/function, using a combination of biochemical, immuno-cytochemical and electrophysiological approaches in in-vitro and cell culture model systems. Specifically, the proposed experiments aim to (1) characterize the mechanistic aspects of GilZ inhibition of ERK, (2) elucidate the mechanistic basis and physiological relevance of GilZ and ERK regulation of ENaC function, and (3) examine the molecular mechanisms of GilZ and ERK regulation of ENaC trafficking and open probability. The elucidation of these pathways will likely identify novel approaches for regulating this process in disease states such as congestive heart failure, metabolic syndrome and salt-sensitive hypertension. In addition to the proposed experiments, didactic coursework in signal transduction, membrane transport, and the responsible conduct of research will complement the structured training program to assist the candidate in achieving her long-term goal for an academic career as a successful research scientist in the field of ion transport and epithelial cell signaling. Dr. Pearce, a leader in the field of hormonal regulation of ion transport, will directly mentor the candidate's scientific development. In addition, Drs. Gluck, Mostov, and Humphreys, who are renowned experts in cellular physiology of ion transporters and membrane trafficking, will provide scientific expertise in the design of experiments and interpretation of results. A Professional Development Advisory Committee will also convene at regular intervals to provide appropriate scientific and career support. UCSF thus offers the technical resources, scientific expertise and structured mentoring required for training the candidate for a successful career in her chosen field.